H. Lee Moffitt Cancer Center and Research Institute, Tampa FL.
Vanderbilt-Ingram Cancer Center, Nashville, TN.
Am Soc Clin Oncol Educ Book. 2022 Apr;42:1-12. doi: 10.1200/EDBK_349811.
With the development of immune checkpoint inhibitors, immunotherapy researchers have facilitated substantial progress for patients with mismatch repair deficient/microsatellite instability-high colorectal cancer, which has led to practice changes at a head-spinning pace. However, this benefit has not been translated into microsatellite stable colorectal cancer, which carries the hallmarks of chromosomal instability. So far, clinical trials have not shown any substantial clinical benefits of immune checkpoint inhibitor therapy for patients with microsatellite stable colorectal cancer, which has been disappointing. Recently, combinations of immune checkpoint inhibitors with tyrosine kinase inhibitors and targeted therapies have been investigated for potential synergistic effects that may increase antitumor activity in the tumor microenvironment and achieve more substantial clinical and radiologic responses. In this article, we discuss the current state of the science for the use of immune checkpoint inhibitors in microsatellite stable colorectal cancers, and we review the molecular underpinnings of inherited physiologic barriers for the delivery of effective immunotherapy. We also elaborate on existing therapeutic opportunities to convert microsatellite stable colorectal cancer into an "immune hot" cancer, which may define the future treatment paradigm of colorectal cancer for which there is a great unmet need.
随着免疫检查点抑制剂的发展，免疫治疗研究人员为错配修复缺陷/微卫星不稳定高结直肠癌患者带来了实质性进展，这使得实践在令人眩晕的速度上发生了变化。然而，这种益处尚未转化为微卫星稳定的结直肠癌，后者具有染色体不稳定性的特征。到目前为止，临床试验并未显示免疫检查点抑制剂治疗对微卫星稳定结直肠癌患者有任何实质性的临床获益，这令人失望。最近，研究了免疫检查点抑制剂与酪氨酸激酶抑制剂和靶向治疗的联合应用，以探索潜在的协同作用，这些作用可能会增加肿瘤微环境中的抗肿瘤活性，并实现更实质性的临床和影像学反应。在本文中，我们讨论了免疫检查点抑制剂在微卫星稳定结直肠癌中的应用的科学现状，并回顾了有效免疫治疗的遗传生理障碍的分子基础。我们还详细阐述了现有的治疗机会，以将微卫星稳定结直肠癌转化为“免疫热”癌症，这可能为存在巨大未满足需求的结直肠癌定义未来的治疗模式。
